Reduction of 11alpha-acyloxy pregnenes



REDUCTION OF Ila-ACYLOXY PREGNENES Alan H. Nathan and John A. Hogg,Kalamazoo Township, Kalamazoo County, Mich., assignors to The UpjohnCompany, Kalamazoo, Mich., a corporation of Michigan No Drawing.Application August 28, 1952, Serial No. 306,941

11 Claims. (Cl. 260-3973) This invention relates to certain steroidcompounds and is more particularly concerned with a process for theproduction and use of 11a-acyloXypregnane-3,20-diones and with certainnovel steroids produced therefrom.

This application is a continuation-in-part of Serial Number 244,744,filed August 31, 1951, now Pat. No. 2,647,134.

It is an object of the present invention to provide a process for theproduction of 1la-acyloxypregnane-ESJO- diones, especially the normalisomer thereof. Another object is the provision of a process for theproduction and use of 11a-acyIOXypregnane-B,20-di0nes. A further objectis the provision of a process, in the preparation ofpregnane-3,11,20-trione, for the production and use of the novelpregnane-3u,1la,20-triol and the novel 11aacyloxypregnane-3a,20-diol,which are prepared from 11oc-acyloXypregnane-3,ZO-diones by reduction.Another object of the invention is the provision of a process for theproduction of the useful pregnane-3,11,20-trione in high yields fromlla-hydroxyprogesterone by a unitary procedure which proceeds throughlla-acyloxyprogesterones and in which all of the steps cooperate, orintegrate to avoid certain problems present in previously availableprocedures for attainment of this result. Other objects will be apparentto those skilled in the art to which this invention pertains.

According to the present invention, lla-acyloxypregnane-3,20-diones,especially the normal isomer thereof, are prepared by the hydrogenationof an lla-acyloxyprogesterone in the presence of a palladiumhydrogenation catalyst. The 11a-acyloXypregnane-3,20-diones are thenconverted, in substantially quantitative yields, to the novelpregnane-3a,11a,20-tricl by reduction and hydrolysis, with possibleproduction of the novel intermediate pregnane11a-acy1oxypregnane-3,ZO-diol. The pregnane-3a,- llu,20-triol iscomgerted by oxidation to the known pregnane-3,11,20-trione. Thecomplete reaction sequence is illustrated graphically by the followingformulae:

2,751,397 Patented June 19, 1956 Thus, pregnane-3,1l,20-trione, whichcan be converted to cortisone acetate by methods known in the art, isprepared in high yield from lla-hydroxyprogesterone. For example,pregnane-3,11,20-trione can be selectively hydrogenated according to theprocedure of Reichstein et al. [Von Euw, Lardon and Reichstein, Helv.Chim. Acta, 27, 821 (1944)] to yield pregnane-3-ol-11,20-dione, whichcan be converted to cortisone acetate by the method of Gallagher andco-workers lKritchevsky, Garmaise and Gallagher, J. Am. Chem. Soc., 74,483 (1952) An alternate and apparently equivalent route topregnane-3,11,20-trione from lloc-hydroxyprogestero-ne would appear tobe by hydrogenation of lla-hydroxyprogesterone, Without acylation,followed by oxidation. In utilizing either such route or the presentroute in the preparation of pregnane-3,11,20-trione fromllu-hydroxyprogesterone, the important step is the saturation, withhydrogen, of the double bond in the 4(5)-position so that the resultinghydrogenated product will have the normal configuration at the5-position. According to the method of the present invention,hydrogenation of the 4(5)- double bond results in the production of thenormal isomer in high yields.

Production of the normal isomer, and in such high yields, is whollyunexpected in view of the prior art experience which shows thathydrogenation of the double bond in the 4(5)-position generally resultsin the formation of the allo configuration at carbon atom five or amixture of the normal and allo configurations with the allo formpredominating lButenandt, Tscherning and Hanisch, Berichte, 68, 2097(1935); Butenandt and Fleischer, Berichte, 68, 2094 (1935)]. A recentreport by Pataki, et al., J. Biol. Chem, 195, 751 (1952) showed that thecatalytic hydrogenation of ll-oxygenated A -3-ketosteroids leads chieflyto the allo isomer. It was found that hydrogenation of corticosteroneacetate (11p-hydroxy-21-aceteary-progesterone)- with a ten per centpalladium-barium sulfate, catalyst gave seventy per cent of the alloisomer;

hydrogenation of ll-ketoprogesterone in a similar manner gave 68 percent of the pure allo isomer; hydrogenation of Kendalls Compound Facetate (11,8,17a-dihydroxy-21- acetoxyprogesterone) gave 82 per centallo isomer. Hydrogenation of cortisone acetate (11-keto-17a-hydroxy-21-acetoxyprogesterone) with a ten per cent palladiumbarium sulfatecatalyst gave seventy per cent of the allo isomer [Djerassi, et al., J.Biol. Chem., 194, 115 (1952)]. Similarly, Mason, et al., J. Biol. Chem.,120, 733 (1937), report a yield of eighty per cent of the allo isomerwhen hydrogenating dehydroco-rticosterone(ll-keto-Zl-hydroxyprogesterone) with hydrogen in the presence ofpalladium black catalyst.

Although hydrogenation of either lla-hydroxyprogesterone or anlla-acyloxyprogesterone yields predominantly the normal isomers, we havefound that hydrogcnating llot-acyloxyprogesterones with hydrogen in thepresence of a palladium catalyst results in higher yields of product ofthe normal configuration at the -position than when the llwacyloxy groupis not present. When following the method of the present invention,hydrogenation of an lla-acyloxyprogesterone, e. g.,Ila-acetoxyprogesterone, with a 7.5 per cent palladium-zinc oxide-zinccarbonate catalyst in methanol results in a quantitative yield ofhydrogenation product assaying 95 per cent 11a-acetoxypregnane,ZO-dioneand only five per cent 11a-acetoxyallopregnane-El,20-dione. Similarly,improved yields of product of the normal configuration are obtained whenusing other palladium catalysts than are obtained when the samecatalysts are used in the hydrogenation of starting compounds having thefree llahydroxy group. Since the yield of normal hydrogenated product ishigher when an llot-acyloxyprogesterone is hydrogenated than whenlla-hydroxyprogesterone is hydrogenated, and sincellu-acyloxyprogesterones can be prepared in sometimes quantitative yieldfrom Ila-hydroxyprogesterone, acylation of llot-hydroxyprogesteroneprior to hydrogenation is therefore a method of convertinglla-hydroxyprogesterone to the normal pregnane series in higher yieldthan by direct hydrogenation of 110:- hydroxyprogesterone.

The fact that the hydrogenation of lloc-acyloxyprogesterone resultsmainly in the formation of the isomer having the normal configuration atthe 5-position is of considerable commercial significance and utility.The present state of the art shows that in the preparation ofphysiologically active adrenal hormones such as, for example, cortisonefrom A -pregnene compounds, it is necessary to eliminate the double bondwhile other transformations are accomplished in the molecule. When thesetransformations, i. e., formation of the desired sidechain,establishment of the desired group at position 11, and the like, areaccomplished, the double bond is again introduced at the 4(5)-position.This step of reestablishing the double bond is dependent on theconfiguration of the molecule at position 5. Compounds with the alloconfiguration can be converted to the 4(5)unsaturated compounds onlywith difficulty and in low yields, whereas in compounds with the normalconfiguration the double bond at the 4(5)-position can be formed easilyand in good yields (U. S. Patent 2,590,993).

Since the known physiologically active adrenal cortical hormones possessan ll-keto function or an ll-hydroxy function, a desirable process forthe use of 11a-acyloxypregnane-3,20-diones includes the conversion ofthe 11eracyloxy group to an Ila-hydroxy or ll-keto group. Logically,saponification of the ester group would seem the best means of achievingthis end. However, hydrolysis of the ester group to a hydroxy group witheither acid or base always appears to cause at least some concommitantinversion of the side-chain to yield 17-iso pregnane compounds asevidenced by the reduced optical rotation of the product. The yield ofdesired product is therefore somewhat reduced. A convenient procedurefor preventing. this inversion of the side-chain is by reducing the 20ketone to a 20-hydroxy group before hydrolysis is attempted. This isachieved, and frequently in quantitative yield, by treatment of an11a-acyloxypregnane-3,20-dione with a reducing agent such as, forexample, a large excess of sodium borohydride, or the like, in methanolor other alkanol, to reduce both the 3- and the ZO-keto groups. Theresulting 11u-acyloxypregnane-3a,20-diol can then be safely treated witha base to saponify the ll-acylate and give pregnane-3,l1,20-triol.Alternatively, pregnanc- 3oz,llot,20-tfi0l can be prepared by treatingllot-acyloxypregnane-3,2Q-dione with lithium aluminum hydride andthereafter decomposing the complex with water, or slightly acidic orbasic aqueous solution. The known pregnanc- 3,11 ,20-trione is thenprepared by contacting pregnanc- 3ct,lltx.,2()triol with about threeequivalents of an oxidizing agent.

The starting steroid for the production of anllaacyloxypregnane-3,20-dione is an lla-acyloxyprogesterone wherein theacyloxy group has the formula AcO, Ac being the acyl radical of anorganic carboxylic acid, which in turn may be prepared by treatment oflloc-l'lYdlOXY- progesterone [Peterson and Murray, I. Am. Chem. Soc.,74, 1871 (1952)] with an acylating agent.

In carrying out the process of the present invention,lla-acyloxyprogesterone, wherein the acyloxy group has the formula AcO,Ac being the acyl radical of an organic carboxylic acid, is contactedwith hydrogen in the presence of a palladium hydrogenation catalyst suchas, for example, palladium black, palladium on charcoal,palladium-barium sulfate, palladium on an ion exchange resin, palladiumon calcium carbonate, palladium in the presence of zinc oxide, zinccarbonate, cadmium oxide, or the like, with or without added base, toproduce an llot-acyloxypregnane-3,20-dione. Sincella-acetoxyprogesterone hydrogenates well and is readily prepared inpractically quantitative yield from llot-hydroxyprogesterone,11aacetoxyprogesterone is a preferred starting steroid. A preferredgroup of hydrogenation catalysts consists of palladium in the presenceof a compound selected from the group consisting of the carbonate,oxide, and mixtures of the carbonate and oxide of a group 2B element ofthe periodic table, i. e., zinc, cadmium, and mercury, said catalystsinfluencing the hydrogenation in such a manner as to produceconsistently high yields of product of the normal configuration. Ofthese catalysts, a palladium-zinc oxide catalyst consisting of fromabout five to about ten per cent by weight of precipitated palladium ispreferred. Some of the above described palladium catalysts sometimesappear to be poisoned during the hydrogenation and the hydrogenationceases prior to completion. Removal of the poisoned catalyst, shakingthe partially hydrogenated solution with Raney nickel, and thencontinuing the hydrogenation with fresh catalyst is a satisfactoryprocedure to obtain complete hydrogenation when this occurs.

The above described hydrogenation appears to proceed well in a solventconsisting of an alkanol containing from one to eight carbon atoms,inclusive, particularly methanol, and one of these solvents is thereforeemployed in preferred operating conditions, although solvents such as,for example, ether acetic acid, or the like, may also be employed.

As previously stated, the structure of lla-acyloxypregnane-3,20-dionecan be altered to prevent inversion of the side-chain by contacting thesteroid with a reducing agent to convert the 3- andthe 20-keto groups to3aand ZO-hydroxy groups, thus rendering the side-chain of the moleculestable to inversion by acid or base. Reducing agents preferred incarrying out the conversion of the keto groups to hydroxy groups arelithium aluminum hydride, sodium borohydride, lithium borohydride, andhydrogen in the presence of a hydrogenation catalyst such as, forexample, Raney nickel, palladium, platinum, or the like.1la-acyloxypregnane-3u,20-diols can be produced by the reaction of11a-acyloxypregnane-El,20-diones with sodium borohydride.Pregnane-3u,l1u,20-triol can be produced by the reaction of11a-acyloxypregnane-3,20- dione with lithium aluminum hydride. In eithercase, pregnane-3a,l1a,20-triol can be prepared by reacting11aacyloxypregnane-3,20-di0ne with a reducing agent, for example,lithium aluminum hydride, sodium borohydride, lithium borohydn'de, orhydrogen in the presence of a hydrogenation catalyst, and thereaftercontacting the reduction mixture with a hydrolyzing agent. Hydrolyzingagents which may be employed include dilute bases and acids such as, forexample, sodium hydroxide, sodium carbonate, hydrochloric acid, andothers.

A particularly advantageous procedure for the preparation ofpregnane-3a,lla,20-triol involves hydrogenating llu-acyloxyprogesteronein an alkanol, preferably methanol, removing the hydrogenation catalystand replacing it with sodium borohydride, preferably in excess to theamount theoretically required to reduce the 3- and 20-keto groups withadded water, if desired, and thereafter refluxing the reduction mixtureafter adding a hydrolyzing agent such as, for example, sodium hydroxide,thereto. This preferred procedure produces, in high yield, pregnane-3a,lla,20-triol from lla-acyloxyprogesterone without the necessity ofintermediate purification or isolation, as shown in the examplesfollowing in this specification. Pregnane-fila,lle,20-triol can bereadily converted by an oxidizing agent, for example, chromium trioxide,chromic acid, or potassium dichromate to the knownpregnane-3,l1,20-trione.

The followin examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting.

PREPARATION 1.PALLAD1UM CATALYST SUPPORTED 0N ZINC OXIDE-ZINC CARBONATBMIXTURE Eleven grams of anhydrous zinc chloride were dissolved in 100milliliters of water at seventy degrees centigrade and a twenty per centaqueous solution of sodium carbonate was added in excess, with constantstirring, forming a precipitate of zinc carbonate. The precipitate wasfiltered, washed free of alkali with warm water, and re-suspended in 100milliliters of water forming a slurry. To the aqueous slurry was addedfive milliliters of a palladium chloride solution containing 0.1 gram ofpalladium per milliliter and then one milliliter of a thirtyseven percent aqueous formaldehyde solution. The resulting red-brown coloredmixture was warmed on a steam-bath to about sixty degrees centigrade anda thirty per cent aqueous solution of sodium hydroxide was addeddropwise with continual stirring, until the pH of the mixture reachednine, at which point palladium precipitated. The black-coloredprecipitate was washed by decantation with ten successivefifty-milliliter portions of water. and then filtered under suction. Theprecipitate on the filter funnel was washed six times, dried by suction,and heated in an oven at 210 degrees centigrade for eleven hours. Sixand eight-tenths grams of a brown-colored catalyst consisting ofpalladium supported on a zinc-oxide zinccarbonate mixture was obtained.

In a similar manner, and omitting the heating, a palladium on zinccarbonate catalyst was obtained. Likewise, palladium supported onmercury carbonate and palladium supported on cadmium carbonate catalystsare prepared. Other catalyst carriers or supports which can be preparedin this manner include the ion exchange resins such as, for example,Amberlite IRA 410, calcium carbonate, barium carbonate, barium sulfate,carbon, and others.

A. PRODUCTION OF lla-ACYLOXY- PROGESTERONES Example 1 .-1 1ot-acetoxyprogesterone To a solution of 100.0 grams (0.304 mole) of110:- hydroxyprogesterone [Peterson and Murray, I. Am.

6 Chem. Soc, 74, 1871 (1952)] in 450 milliliters (4.7 moles) of aceticanhydride was added 45 milliliters of pyridine whereafter the whole washeated on a steambath for eighty minutes. The cooled reaction mixturewas thereafter poured into four liters of ice and Water and the wholewas kept in a refrigerator for two days. The precipitatedllet-acetoxyprogesterone was then filtered, twice re-slurried with waterand refiltered, and thereafter dried in vacuo at seventy degreescentigrade for three hours. The dried lla-acetoxyprogesterone weighed110.5 grams, a yield of 98 per cent of the theoretical, and melted at172 to 176 degrees centigrade.

Example 2.11a-formyloxyprogesterone One gram of lla-hydroxyprogesteronein twenty milliliters of 87 per cent formic acid was heated for twohours at 75 degrees centigrade. Upon incorporating 200 milliliters ofwater thereto, there precipitated 0.92 gram of crystals melting at 152to 154 degrees centigrade. Two recrystallizations from forty-milliliterportions of 45 per cent formic acid gave 1lwformyloxyprogesteronemelting at 158.5 to 161.5 degrees centigrade.

Example 3.] 1 a-propionyloxyprogesterone A mixture of 6.70 grams oflla-hydroxyprogesterone, thirty milliliters of propionic anhydride andthirty milliliters of pyridine was maintained at room temperature forabout twenty hours. The solution was then poured into five hundredmilliliters of ice water whereupon a colorless gum formed which sooncrystallized. After hydrolysis of the excess propionic anhydride hadoccurred, the crystalline lle-propionyloxyprogesterone, was collected,washed thoroughly with water, dried in air and thereafter in a vacuumdesiccator over calcium chloride. The yield of 7.60 grams was 97.5 percent of the theoretical. The thus-produced 1la-propionyloxyprogesteronehad a melting point of 145.5 to 146 degrees centigrade and an opticalrotation [011 of plus 156 degrees (chloroform).

Analysis-Percent calculated for Carl-13404: C, 74.58; H, 8.87. Found: C,74.84; H, 8.74.

Example 4 .1 I ot-benzoyloxyprogesterone llot-hydroxyprogesterone (0.5gram) was dissolved in six milliliters of hot benzene and cooled to roomtemperature. Then 0.4 milliliter of freshly dried and redistilledpyridine and 0.4 milliliter of freshly-distilled benzoyl chloride wasadded and the mixture allowed to stand at room temperature for twentyhours. The reaction mixture was diluted with fifty milliliters of ether,washed successively with water, and ten per cent sodium hydroxidesolution, and finally with water. The solution was then dried oversodium sulfate and the solvent was thereafter evaporated on a hot waterbath, the terminal evaporation being facilitated by vacuum. The residuewas heated with 25 milliliters of water under reflux for fifteenminutes, cooled, extracted with ether, washed with water, a ten per centsodium hydroxide solution, and again with water, dried and evaporated toa volume of ten milliliters. After cooling the solution, the crystalswhich formed during the evaporation were removed by filtration andwashed with about five milliliters of hexane. The yield was 0.44 gram(68 per cent of the theoretical) of llot-benzoxyprogesterone melting at179 to 181 degrees centigrade. Recrystallization from ten milliliters ofether gave a product melting at 181 to 183 degrees centigrade; [111 ofplus 88 degrees (chloroform) Analysis.-Percent calculated forCasi-13404: C, 77.38; H, 7.89. Found: C, 77.50; H, 7.88.

lla-hydroxyprogesterone can be converted into the correspondinglla-acyloxy derivatives as indicated in Examples 1 to 4, by reactionwith an acid anhydride or acyl halide, in an organic solvent such aspyridine or the like, with ketene or a ketene of a selected acid.Representative esters of llot-hydroxyprogesterone thus prepared includeesters of malonic, maleic, succinic, glutaric and adipic acids, and oneto eight carbon atom carboxylic acid acyloxy esters of other aliphaticor cycloaliphatic, aryl, alkaryl, aralkyl, mono, di or polycarboxylicacids, wherein the acyloxy group of the thus-producedllaacyloxyprogesterone is, for example, formyloxy, acetoxy,propionyloxy, butyryloxy, valcryloxy, hexanoyloxy, heptanoyloxy,octanoyloxy, benzoxy, phenylacetoxy, toluoyloxy, naphthoyloxy,cyclopentanoyloxy, cyclopentylpropionyloxy, acrylyloxy,cyclohexanoyloxy, and the like. The acyl groups may also containnon-interfering substituents, such as mono or poly, halo, chloro, bromo,hydroxy, methoxy, or the like, if desired.

B. HYDROGENATION OF llcx-ACYLOXYPROGES- TERONES TO1la-ACYLOXYPREGNANE-3,20- DIONES Example 5.] 1oa-acetoxypregnane-S,ZO-dione A solution of 200 grams oflloc-acetoxyprogesterone, prepared according to Example 1 and melting at172 to 176 degrees centigrade, in 1200 milliliters of absolute methanolwas stirred with 25 grams of Raney nickel for two hours at roomtemperature Whereafter the Raney nickel was filtered and the filtrateconcentrated to 750 milliliters by distillation. The concentratedsolution was hydrogenated in the presence of a 7.5 per cent palladium onzinc oxide catalyst at a hydrogen pressure of twenty pounds. Hydrogenabsorption ceased after one third of the theoretical amount of hydrogenhad been absorbed. The catalyst was then filtered, the filtrate diultedto 3.5 liters With absolute methanol and the solution stirred once morewith 100 grams of Raney nickel. The Raney nickel was filtered, thefiltrate concentrated to 750 milliliters by distillation andhydrogenation was continued in the presence of 100 grams of the 7 .5 percent palladium on zinc carbonate catalyst until the theoretical amountof hydrogen had been absorbed. The catalyst was then filtered and washedwith 100 milliliters of warm absolute methanol and the combined filtrateand wash were distilled to dryness. The residue of lla-acetoxypregnane-3,20-dione, after drying at 75 degrees centigrade in vacuo for threehours, Weighed 203.4 grams, a quantitative yield of product.

Example 6.11a-acetoxypregnane-S,ZO-dione Three grams ofllot-acetoxyprogesterone was hydrogenated at a hydrogen pressure ofabout ten pounds in 100 milliliters of absolute methanol in the presenceof a 7.5 per cent palladium on zinc carbonate catalyst. Whenhydrogenation was complete and the methanol filtrate, obtained byfiltration of the catalyst, was evaporated, a quantitative yield ofhydrogenated product was obtained melting at 145 to 149 degreescentigrade. A melting point curve of known mixtures of pure allo andnormal 11wacetoxypregnane-3,20-dione indicated that the productconsisted of about 95 per cent normal lla-acetoxypregnane-3,20-dione.

Example 7.-11a-acet0xypregnane-3,20-di0ne In the same manner asdescribed in Example 6, 1.21 grams of lla-acetoxyprogesterone Washydrogenated in 100 milliliters of absolute methanol in the presence ofa ten per cent palladium on zinc carbonate catalyst. Isolation in thesame manner as described above gave a quantitative yield of productmelting at 133 to 146 degrees centigrade, indicating that the productcontains about ninety per cent normal 1la-acetoxypregnane-3,20- dione.

Example 8 .-1 1 ot-acetxypregnane-3,2O-dione In the same manner asdescribed in Example 6, 3.33 grams of lle-acetoxyprogesterone washydrogenated in methanol in the presence of 0.1 gram of a thirty percent palladium on charcoal catalyst. Isolation of the hydro- '8 genationproduct gave a quantitative yield of product assaying about per centnormal lle-acetoxypregnane- 3,20-dione.

Example 9.-] 1 u-acetoxypregnane-3,2O-di0ne In the same manner asdescribed in Example 6, 3.33 grams of lla-acetoxyprogesterone washydrogenated in methanol in the presence of one gram of a ten per centpalladium on calcium carbonate catalyst and one milliliter of Triton Btrimethylbenzylammonium hydroxide. The quantitative yield of productassayed about 88 per cent normal 11a-acetoxypregnane-3,20-dione.

Example 10.-11a-propionyloxypregnane-3,20-di0ne In the same manner asdescribed in Example 6, 11- propionyloxyprogesterone is hydrogenated inthe presence of a palladium on charcoal catalyst in methanol to give aquantitative yield of hydrogenated product consisting essentially of1la-propionyloxypregnane-3,20-dione.

Example 11 .1 1 a-benz0xypregnane-3,20-dione In the same manner asdescribed in Example 6, 11ozbenzoxyprogesterone is hydrogenated in thepresence of a palladium on cadmium carbonate catalyst in methanol togive a quantitative yield of hydrogenated product consisting essentiallyof 11ca-benzoxypregnane-li,20-dione.

In the same manner as given in Examples 1 through 11, otherlla-acyloxyprogesterones are hydrogenated in the presence of a palladiumcatalyst such as, for example, palladium, palladium on carriers such as,for example, calcium oxide, cadmium oxide, zinc carbonate, Zinccarbonate-zinc oxide, cadmium carbonate, charcoal, palladium in thepresence of zinc carbonate, or the like, in an organic solvent such as,for example, acetone, methyl ethyl ketone, hexane, ethanol, methanol, orthe like, preferably an alcohol, to produce a hydrogenated product richin the desired hydrogenated product of the normal configuration.Compounds thus-hydrogenated include la-formyloxyprogesterone, l1a-butyryloxyprogesterone, l 1a-valeryloxyprogesterone, 1lot-hexanoyloxyprogesterone, 1 1ot-heptanoyloxyprogesterone, llot-OCiElnOYlOXYPIO- gesterone, and others.

C. REDUCTION OF Ila-ACYLOXYPREGNANE- 3,20-DIONES Example12.pregnane-3oc,11 a,20-triol A solution of 202 grams (0.541 mole) of11u-acetoxy pregnane-3,20-dione, obtained according to the methoddescribed in Example 6, in 4.750 milliliters of methanol was mixed with28.1 grams (0.74 mole) of sodium borohydride dissolved in 200milliliters of water. The mixture was stirred and heated for 2.5 hoursat fifty to sixty degrees centigrade whereafter 128 grams of sodiumhydroxide in 430 milliliters of water was added thereto to saponify thethus-produced lla-acetoxypregnane-3a,20- diol, and the heating wascontinued for one hour. The reaction mixture was kept at roomtemperature for sixteen hours whereafter the reaction mixture wasconcentrated by distillation to 3.5 liters and then neutralized withhydrochloric acid. The neutral solution was thereafter distilled untilthe distillation temperature reached 96 degrees centigrade. Thepregnane-3a,11a,20-triol which had precipitated was filtered and driedin vacuo for sixteen hours at 65 degrees centigrade. The yield wasquantitative (184 grams); melting point 193 to 197 degrees centigrade.

Example 13.-pregnane3a,1Za,20-tri0l A solution of 3.745 grams oflloc-acetoxyprogesterone was dissolved in milliliters of anhydrousmethanol and hydrogenated at eleven pounds hydrogen pressure in thepresence of 1.9 grams of palladium on Amberlite IRA 410 resin catalystfor thirty minutes. The catalyst was filtered and washed with methanol.The combined 1 filtrate and wash were mixed with 500 milligrams ofsodium borohydride in five milliliters of water to which had been addedtwo drops of a 2.5 N solution of sodium hydroxide and the Whole refluxedfor one hour whereafter a solution of three grams of sodium hydroxide inten milliliters of water was added thereto. Heating was continued andthe refluxing solution was distilled until the methanol was removed. Theaqueous residue contained white crystals which were filtered, Washedwith Water, and then dried for sixteen hours in a vacuum desiccator. Aquantitative yield of pregnane-3a,11ot,20 triol melting at 181 to 194degrees centigrade was thus obtained.

Example 14.-Pregnane-3a,l 1 a,20-tril A solution of 360 milligrams oflla-acetoxypregnane- 3,20-dione, obtained according to the method ofExample 6, in fifty milliliters of anhydrous ether was mixed with 200milligrams of lithium aluminum hydride whereupon a vigorous reactionensued. After being maintained at room temperature for one-half hour,the reaction mixture was mixed with dilute sulfuric acid until acidic.The ether layer was separated and the aqueous layer Was extracted withan equal volume of ether which Was combined with the ether layer. Thecombined ether layers were washed with a saturated aqueous sodiumchloride solution and then dried over anhydrous sodium sulfate takingcare to thereafter Wash the sodium sulfate thoroughly with ether. Theether was then distilled from the dry solution leaving a quantitativeyield of pregnane- 30c,l1a,20-tfl0l as a white powder.

Example 15.Pregnane-3e,1 1 a,20-trz'o-l In the same manner as describedin Example 13, three grams of 11oc-propionyloxyprogesterone washydrogenated at a hydrogen pressure of eleven pounds in the presence of1.5 grams of a 7.5 per cent palladium on zinc carbonate catalyst in 45milliliters of methanol. The thus-produced1lu-propionyloxypregnane-3,20-dione was reduced in isopropanolcontaining a small amount of water with 0.4 gram of sodium borohydrideto Ila-propionyloxypregnane-3a,20-diol. Treatment of the sodiumborohydride reduction mixture with ten milliliters of a 5 N aqueoussodium hydroxide solution for two hours at the reflux temperature of thereaction mixture and then at about fifty degrees centigrade for sixteenhours yielded upon isolation 3.29 grams, a yield of 95.5 per cent of thetheoretical based upon the starting lla-propionyloxyprogesterone, ofpregnane-3a,l1a,20-triol melting at 180 to 193 degrees centigrade.

In essentially the same manner as described in Examples 12 to 15, the 3-and the 20-keto groups of other 110cacyloxypregnane-3,20-diones arehydrogenated by hydrogenating agents such as, for example, lithiumaluminum hydride, sodium borohydride, lithium borohydride, hydrogen inthe presence of a catalyst such as, for example, Raney nickel, platinum,and others, in a solvent such as, for example, methanol, ethanol,isopropanol, ether, ethyl acetate, benzene, or the like, to produce3ocand 20-hydroxy groups. Treatment of the hydrogenation product with adilute water-methanolic sodium hydroxide solution is productive ofpregnane-3ot,l1a,20-triol. Compounds thus converted topregnane-3oz,lla,20-triol include 1lwformyloxypregnane-ll,20-dione,lla-butyryloxypregnane-3,20-dione, 11a-valeryloxypregnane-3,20-dione,11a-hexanoyloxypregna11e-3,20-dione,lla-heptanoyloxypregnane-3,20-dione, lla-octanoyloxypregnane-3,20-dione, and the like.

One gram of pregnane-3u,11a,20-triol, obtained according to the methodof Example 12, was dissolved in 25 milliliters of boiling chlorobenzeneand the cooled solution was added with cooling to an agitated solutionof 4.5 grams technical sodium dichromate, six milliliters concentratedsulfuric acid, and 25 milliliters water. After stirring for six hours atroom temperature, the chlorobenzene layer was removed, the aqueous layerextracted twice with equal volumes of benzene which were then added tothe chlorobenzene, and the combined chlorobenzene and benzene solutionswere washed with water and a saturated aqueous sodium chloride solution.The solvents were then evaporated by a current of air leaving a900-milligram residue, a yield of ninety per cent of the theoretical, ofpregnane-3,11,2()-trione which, after triturating with a two to onemixture of ether and acetone, melted at 148 to 151 degrees centigrade.

In a similar manner, pregnane-3,11,20-trione is produced frompregnane3a-11a,20-triol by the action of other oxidizing agents such as,for example, potassium dichromate, chromic acid, hydrogen peroxide, orthe like.

It is to be understood that the invention is not to be limited to theexact details of operation or exact com pounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A process for the saturation of the double bond in the 4(5)-positionof an lla-acyloxyprogesterone to produce a high proportion of11a-acyloxypregnane-3,20-dione having the normal stereoconfiguration ofhydrogen at carbon atom five of the steroid nucleus, which comprises:hydrogenating an lla-acyloxyprogesterone wherein the acyloxy group hasthe formula AcO, Ac being the acyl radical of an organic carboxylicacid, with hydrogen in the presence of a palladium hydrogenationcatalyst, to produce an 11a-acyloxypregnane-3,20-dione.

2. The process of claim 1 wherein the hydrogenation catalyst ispalladium in the presence of a compound selected from the groupconsisting of the carbonate, the oxide, and mixtures of the carbonateand oxide of a group 2B element of the periodic table, and wherein thehydrogenation is carried out in the presence of an alkanol containingfrom one to eight carbon atoms, inclusive.

3. A process for the saturation of the double bond in the 4(5)-positionof lla-acetoxyprogesterone to produce a high proportion of1la-acetoxypregnane-3,20-dione having the normal stereoconfiguration ofhydrogen at carbon atom five of the steroid nucleus, which comprises:hydrogenating lla-acetoxyprogesterone with hydrogen in the presence of ahydrogenation catalyst comprising palladium in the presence of acompound selected from the group consisting of the carbonate, the oxide,and mixtures of the carbonate and oxide of a Group 213 element of theperiodic table, to produce lla-acetoxypregnane- 3,20-dione.

4. A process for the saturation of the double bond in the 4(5)-positionof llu-acetoxyprogesterone to produce a high proportion of1la-acetoXypregnane-3,20-dione having the normal stereoconfiguration ofhydrogen at carbon atom five of the steroid nucleus, which comprises:hydrogenating lla-acetoxyprogesterone with hydrogen in the presence of apalladium-zinc oxide hydrogenation catalyst comprising from about fiveto about ten per cent by Weight of palladium, to producella-acetoxypregnane- 3,20-dione.

5. A process for the production of lla-acetoxypregnane3,20-dione,including a high proportion of llaacetoxypregnane-3,ZO-dione having thenormal stereoconfiguration of hydrogen at carbon atom five of thesteroid nucleus, from lla-hydroxyprogesterone, which comprises: mixingllu-hydroxyprogesterone with the acetylating agent to produce11u-acetoxypregnane-3,20- dione and thereafter hydrogenating thethus-produced llu-acetoxyprogesterone with hydrogen in the presence of ahydrogenation catalyst consisting of palladium in the presence of acompound selected from the group consisting of the carbonate, the oxide,and mixtures of the 1 1 carbonate and oxide of a group 2B element of theperiodic table, to produce l1a-acetoxypregnane-3,20-dione.

6. A process which comprises: hydrogenating 8.21 110:-acyloxyprogesterone wherein the acyloxy group has the formula AcO, Acbeing the acyl radical of an organic carboxylic acid, with hydrogen inthe presence of a palladium hydrogenation catalyst to producella-acyloxypregnane-3,20-dione, and thereafter reducing the thusproduced1lot-acyloxypregnane-3,20-dione with a reducing agent to convert the 3-and ZO-keto groups in the molecule to 3aand ZO-hydroxy groups.

7. A process which comprises: hydrogenating 110cacetoxyprogesterone withhydrogen in the presence of a palladium hydrogenation catalyst toproduce 11 oc-acetoxypregnane-3,20-dione and thereafter reducing the110:- acetoxypregnane-3,20-dione with a reducing agent selected from thegroup consisting of hydrogen in the presence of a hydrogenationcatalyst, lithium aluminum hydride, sodium borohydride, and lithiumborohydride to convert the 3- and 20-keto groups in the molecule to3424- and 20- hydroxy groups.

8. A process for the production of pregnane-3a,- lla,20-triol whichcomprises: hydrogenating an 110:- acyloxyprogesterone wherein theacyloxy group has the formula AcO, Ac being the acyl radical of anorganic carboxylic acid, with hydrogen in the presence of a palladiumhydrogenation catalyst to produce llclx-QCYIOXY- pregnane-3,20-dione;removing the hydrogenation catalyst and reducing the hydrogenationproduct with an excess of sodium borohydride to produce anllot-acyloxypregnane-3a,20-diol; and hydrolyzing the thus-produced11m-acyloXypregnane-3a,20-diol to pregnane-3u,1la,20- triol.

9. A process for the production of pregnane-3,1l,20- trione whichcomprises: hydrogenating an Ila-acyloxyprogesterone wherein the acyloxygroup has the formula AcO, Ac being the acyl radical of an organiccarboxylic acid, with hydrogen in the presence of a palladiumhydrogenation catalyst to produce an lla-acyloxypregnane-3,20-dione;reducing the thus-produced lla- 12 acyloxypregnane-3,ZO-dione with areducing agent to convert the 3- and 20-keto groups of the molecule to3&- and ZO-hydroxy groups; hydrolyzing the reduction product to producepregnane-3culla,20-triol; and oxidizing the thus-produced p1'egnane-3oc,11a,20-tfi0l with an oxidizing agent to producepregnane-3,ll,20-trione.

10. A process for the production of pregnane-3,ll,20- trione whichcomprises: hydrogenating lla-acetoxyprogesterone with hydrogen in thepresence of a hydrogenation catalyst comprising palladium in thepresence 01: a compound selected from the group consisting of thecarbonate, the oxide, and mixtures of the carbonate and oxide of a group23 element of the periodic table to produce anlla-acetoxypregnane-I:,ZO-dione; separating the hydrogenation catalystand reducing the thus-produced llot-acetoxypregnane-3,ZO-dione in situwith an excess of sodium borohydride to produce an llot-acetoxypregnane-3a,20-di0l; hydrolyzing the reaction product to producepregnane-Sa,lla,20-triol; and oxidizing the thus-producedp16g112tI16-3oc,11oc,20-111fi01 with about three equivalents of chromicacid to produce pregnane-3,ll,20-trione.

11. A process for the production of a pregnane-3,ll,20- trione whichcomprises: mixing lla-hydroxyprogesterone with an esterifying agent toproduce an Ila-acyloxyprogesterone wherein the acyloxy group has theformula AcO, Ac being the acyl radical of an organic carboxylic acid;hydrogenating the l1a-acyloxyprogesterone with hydrogen in the presenceof a palladium hydrogenation catalyst to produce anlla-acyloxypregnane-3,ZG-dione; reducing thella-acyloxypregnane-3,ZO-clione with a reducing agent to convert the 3-and ZO-lifitO groups in the molecule to 30cand ZO-hydroxy groups;hydrolyzing the reaction product to produce pregnane-3a,l let,20-triol;and contacting the thus-produced pregnane-3m,lla,20-triol with aboutthree equivalents of an oxidizing agent to producepregnane-3,11,20trione.

References Cited in the file of this patent Pieser et a1.: NaturalProducts Related to Phenanthrene, 3rd Ed., pp. 98, 99, and 417-422(1949).

1. A PROCESS FOR THE SATURATION OF THE DOUBLE BOND IN THE 4(5)-POSITIONOF AN 11A-ACYLOXYPROGESTERONE TO PRODUCE A HIGH PROPORTION OF11A-ACYLOXYPREGNANE-3,20-DIONE HAVING THE NORMAL STEREOCONFIGURATION OFHYDROGEN AT CARBON ATOM FIVE OF THE STEROID NUCLEUS, WHICH COMPRISES:HYDROGENATING AN 11A-ACYLOXYPROGESTERONE WHEREIN THE ACYLOXY GROUP HASTHE FROMULA ACO, AC BEING THE ACYL RADICAL OF AN ORGANIC CARBOXYLICACID, WITH HYDROGEN IN THE PRESENCE OF A PALLADIUM HYDROGENATIONCATALYST, TO PRODUCE AN 11A-ACYLOXYPREGNANE-3,20-DIONE.